Age Related Macular Degeneration

Emerging Technologies

Waldemar Torres, MD, FACS

VITREO-RETINAL SURGEON

NATIVE FROM PUERTO RICO

TRAINED IN THE UNIVERSITY OF PUERTO RICO AND PONCE SCHOOL OF MEDICINE, P.R.

INTERSHIP IN STATE UNIVERSITY OF NEW YORK, BINGHAMTON, N.Y.

OPHTHALMOLOGY TRAINING AT THE ALBERT EINSTEIN COLLEGE OF MEDICINE / YESHIVA UNIVERSITY, BRONX, NY

SUB-SPECIALTY TRAINING AT SOUTH TEXAS RETINA CONSULTANTS, CORPUS CHRISTI, T.X.

MEDICAL PRIVILEGES AT: SARASOTA MEMORIAL HOSPITAL VENICE REGIONAL HOSPITAL DOCTORS HOSPITAL LAKEWOOD RANCH HOSPITAL ST. ANDREWS OUTPATIENT SURGERY CENTER

FELLOW OF THE AMERICAN COLLEGE OF SURGEONS

FELLOW OF THE AMERICAN ACADEMY OF OPHTHALMOLOGY

DIPLOMATE OF THE AMERICAN BOARD OF OPHTHALMOLOGY

MEMBER OF THE PAN AMERICAN ASSOCIATION OF OPHTHALMOLOGY

MEMBER OF THE SARASOTA MEDICAL SOCIETY

MEMBER OF THE AMERICAN MEDICAL ASSOCIATION

MEMBER OF THE FLORIDA OPHTHALMOLOGY ASSOCIATION

MEMBER OF THE HILLSBOROUGH COUNTY OPHTHALMOLOGY SOCIETY

Age-Related Macular

Degeneration Known as macular degeneration, AMD, ARMD

Approximately 15 million people in the USA have AMD

Described more than 80 years ago by Holloway TB, Verhoeff, Trans Am Opth Soc 1928

AMD is a chronic, progressive disease of the macula (central portion of retina) that destroys central vision required for reading, driving, cooking, facial recognition and other common tasks

Leading Cause of Vision

Loss AMD is the leading cause of severe vision

loss & blindness in adults over age 50 [1] in the western world

It is a global public health problem

The general consensus is that as the population grows and ages, the incidence will increase as well

The main cause of vision loss in AMD is the development of choroidal neovascularization or abnormal blood vessel growth, also known as wet AMD[1] Early Detection & Treatment of Neovascular AMD,

Bressler, JABFP 2002

AMD Types

Dry AMD Wet AMD (non-neovascular) (neovascular)

Dry AMD Accounts for the majority of AMD cases

Early stage can be very mild at first

Progressive degeneration of the RPE ( retinal pigment epithelium) and the photoreceptor loss (the light sensitive cells) and subsequent vision loss

When the patient loses most of the central vision, this central spot or degeneration is called geographic atrophy ( GA) or the end stage of it,

The progression varies between individuals, with vision loss occurring more quickly in some than in others as the tissue in the macula degenerates

Wet AMD: A Rapid Descent

TIME

Wet AMD

Blindness

Severe Vision Loss

Early Intermediate Advanced

(dry) (dry) (wet)

No Vision Loss

Today: many are

diagnosed after vision

loss

There are no good predictors

for who will develop Wet AMD

or when

Wet AMD is a debilitating disease that can result in

rapid deterioration of your central vision

Wet AMD

Imbalance of: pro-angiogenic factors that induce new blood

vessels formation angiogenic inhibitory factors that inhibit new

blood vessels formation

Excess production of VEGF (vascular endothelial growth factor)

Growth of “ abnormal blood vessels” or a choroidal neovascular membrane leading to scar formation

Wet AMD

New blood vessels grow beneath the retina

Leak blood & fluid

Damage photoreceptors ( the light sensitive cells at the back of the eye) causing permanent vision loss

Risk of Conversion to Wet AMD

43% of patients who already have wet AMD in one eye will develop wet AMD in their other eye within 5 years [1]

26.4% of patients with intermediate (dry) AMD in both eyes will develop wet AMD within 5 years [1]

6.3% of patients with intermediate (dry) AMD in one eye will develop wet AMD within 5 years [1]

[1] AREDS Report No. 11, Arch Ophthalmol, 2003

Treatment for advanced dry AMD

(GA) AMD is a complex disease with various pathologic

mechanisms

Current strategies pursued by researchers are:

New drugs that aim to prevent damage to the retina or to slow the progression of dry AMD Anti-inflammatory drugs Complement inhibition ( inhibition of a immune system

pathway) Alleviation of oxidative stress ( anti oxidants use) Reduction of accumulation of retinal toxins Enhancement of choroidal blood perfusion ( improving

circulation of retinal circulation)

Sirolimus ( Rapamycin): anti fungal and immuno-supressant agent Various phase1/2 clinical trials sponsored by

National Eye Institute has been completed Subconjunctival injection every 2 months for

dry AMD Patients with geographic atrophy Another study is using an oral dose along

with other agents for wet AMD Results will be available shortly

Fluocilonolone Acetonide Intra-vitreal implant Synthetic hydrocortisone derivative implant

inside the eye Sustained release for up to 36 months Ongoing Phase 2 trial is enrolling patients

with bilateral GA Will assess the rate of GA progression in a 2-

year span. This is a medicine secreting implant to protect

dying retinal cells

POT-4 Designed to inhibit the complement activation

system ( an immune system pathway) Intra-vitreal gel sustained release system Neutralize early AMD inflammatory

component A phase 1 study was completed and a phase

2 study is being pursued

ARC1905 ( C5 inhibitor aptamer) Prevents C5a production Eyes with dry AMD stains for C5a in

histopathological studies Possible benefit in blocking this agent A phase 1 study was recently completed Intra-vitreal injection Results not yet available

Eculizumab An antibody against C5 Currently FDA approved for paroxysmal nocturnal hemoglobinuria Phase 2 study

NT501 Genetically modified RPE intra-vitreal implant Overexpresses ciliary neurotrophic factor, a growth factor

capable of retarding cellular and functional losses in RPE and photoreceptors in neurodegenerative diseases

A phase 2 study reported visual stabilization in 96.3% of treated eyes vs. 75% of control eyes

Improvement in retinal thickness was observed as early as 4 months

It received a FDA fast track designation for the treatment of visual loss associated with GA

AL-8309A Has shown capacity to decrease oxidative

damage in animal studies of light-induced damage

Similar changes has been found in patients with dry AMD

Potential candidate Phase 2 study Topical solution for possible prevention of GA

progression as well as visual acuity changes 0ver 2-year span

Reduction of retinal toxins

Studies have shown that there is an accumulation of lipofuscin, a waste product at the leading edge of the lesion in dry AMD

It precedes the spreading of the lesion and death of retinal tissue

To slow or stop progression of GA

ACU-4429 and Fenretinide were developed to prevent the accumulation of lipofuscin

Oral doses

Phase 1 and 2 studies ongoing

Accutane is a possible candidate

Choroidal blood perfusion enhancers Reduction in choroidal blood flow is more

pronounced in patients with AMD

Alprostadil Intra-venous injection to try to improve macular

blood flow The drug failed to reach the primary outcome

MC-1101 Topical drug that has been shown to increase mean

choroidal blood flow Compelling results from a Phase 1 study have led to

a fast track FDA designation for further development of the drug

Other AMD Risk Factors

Age

Genetics

Ethnicity

Gender

Diet - modifiable

Smoking - modifiable

AREDS 2 study

The original AREDS study established that anti-oxidants, zinc supplements or a combination of both can result in a reduction in risk for AMD progression in patients at high risk

Omega 3 fatty acids in this study population given as a 1- gram dose do not appear to have any beneficial effect on preventing progression to wet AMD

Lutein and zeaxanthine , although showing no statistically significant advantage for preventing AMD progression, are reasonable substitutes for beta carotene due the increased risk of lung cancer associated with beta carotene

AREDS 2 supplement

Vitamin C 500 mg

Vitamin E 400 IU

Copper 2 mg

Zinc 80 mg

Lutein 10 mg

Zeaxanthine 2 mg

If you are taking several medications you should

consult with your physician

The idea that “ more is better” should be avoided

AREDS 2

18 % reduction in the progression to advanced AMD

22% reduction in the risk of progression to neo-vascular ( wet) AMD

30% reduction in any cataract progression

Major breakthroughs have been made in the last decade in treating the wet form of AMD

The change in near-term prognosis with 90% chance of stabilizing or increasing vision

Significant price tag of monthly intra-vitreal injections

Injection-related adverse events/ risks

Uncertainty of how long the treatment will last or when it can be stopped without risk of recurrence

Importance of Early DetectionOn Treatment for Wet AMD

Now there are treatments for wet AMD which have proven to be effective in halting the progression of wet AMD in most cases.

These treatments consist of injections in the eye.

Clinical studies have shown that these new treatments are generally more effective the earlier they begin, when the patient still has good visual acuity and the lesion is still small.

Intra-vitreal injection

It is performed in the office

Using topical anesthesia (eyedrops and gel) or a subconjunctival anesthesia (injection under the capillaries of the eye)

Under aseptic/ sterile conditions

Very low risk of infection, bleeding inside/outside the eye, cataract, retinal detachment or corneal scratch after the injection

Usually is very comfortable

Treatments for advanced wet AMD

In wet AMD, too much VEGF ( Vascular endothelial growth factor) is produced in the eye

This causes the growth of unwanted, unhealthy blood vessels

Anti-VEGF drugs block the production of VEGF and stop the development of the blood vessels

Ranibizumab ( Lucentis) Genentech, Novartis. Approved by FDA in 2006 Antibody fragment that is injected inside the eye ( intra-vitreal

injection) Has proven its benefits in several clinical trials by stabilizing or

improving the visual acuity in 95% of patients Reduces the retinal thickness and promotes sub retinal fluid

resorption A monthly intra-vitreal dose , approximately $ 2000

Bevacizumab (Avastin, Genentech) Possibly the anti-angiogenic agent most

widely used worldwide Full length antibody against VEGF Approved by the FDA for the treatment of

metastatic colorectal cancer, metastatic breast cancer and non-small cell lung cancer.

Monthly dose ( 1.25 mg) Approximately $ 17-50 month Recent infection outbreak in USA ( 2011) was

linked to a single compounding pharmacy

CATT trial

1,208 patients were randomized

injections of Lucentis vs Avastin

Monthly vs as needed injections with monthly evaluations

They were found to be equivalent on a monthly injection regimen

Aflibercept ( Eylea), Regeneron, Bayer Fusion protein of VEGFR1, VEGFR2 and IgG1

Fc fragment Every month X 3 then every 2 months Trials suggest that it is effective for longer

periods of time

Combination therapy

Targets formation of new blood vessels, inflammation and prevention of scar formation

Goal is to increase the overall efficacy and reduce the need of monthly injections and side effects by allowing the use of lower doses

Radiotherapy Selectively targets new blood vessels Attenuates the inflammatory response Decreases scar formation Initial data by different studies was encouraging decreasing the number

of current injections CABERNET study( 457 eyes)

Failed to demonstrate a visual acuity benefit The future of this treatment modality is uncertain

ORAYA therapy is a combination of anti VEGF plus a single, small dose of radiotherapy, less than 20 minutes total procedure It significantly reduced the need of multiple anti-VEGF

Photodynamic therapy and

steroids In the year 2000, PDT became the first FDA approved

treatment for wet AMD, by being the first treatment to effectively prevent vision loss

Intravenous injection of verteporfin ( light sensitive dye) that travels to the eye

Followed by a laser activation within the lesion

It causes a photochemical reaction, leading to platelet aggregation and local thrombosis ( shutting down the abnormal blood vessels)

Studies showed better visual acuity, stabilization of lesions and less retreatment studies ( PDT with Ranibizumab)

Dexamethasone and triamcinolone High rate of cataract and high ocular pressure Anti scar formation, anti inflammatory and anti new

blood vessels formation

Sunitib, FDA approved for the treatment of renal and gastrointestinal tumors

Oral dose that has shown to reduce laser-induced formation of new blood vessels in mice

Topical (eyedrops) effective decreasing formation of new blood vessels in rabbit corneas

Ongoing studies using intra-vitreal injections

CentraSight lens

Implanted into one eye

Magnifies images, projecting the bigger image onto a healthier part of the retina

Strict screening is necessary

Second Sight An implant that attaches to the outside

surface of the eye and connects to an electrode placed in the retina

A camera mounted on a pair of glasses communicates with the implant

Is in clinical trials in the USA and is already in use in Europe

Acupunture

The theory is that needles placed at certain points release energy to the liver

In traditional Chinese medicine, the liver and gallbladder are thought to control the eyes

The energy supposedly improves the function of the liver and thereby increases the blood supply to the retina

Rigorous controlled testing on a large number of patients is needed

Rheopheresis

Still not a proven therapy for dry AMD

In clinical trials it was shown to be safe but the visual results

were not conclusive

It is similar to kidney dialysis, the patient’s blood is filtered

It removes substances that accumulate in the blood as LDL

cholesterol, fibrinogen and lipoprotein A to promote an

improvement in blood flow and vascular function in the retina

and elsewhere

Microelectrical stimulation

Is being promoted as a therapy for early stages of AMD

TENS ( Transcutaneous Electrical Nerve Stimulation)

Routinely used for alleviation of pain

A low voltage current is delivered through electrodes in contact with the skin overlying key nerves around the eye

The theory is that it improves macular function and aids the removal of potentially harmful waste products

One study reported improvements of vision in patients with AMD but the study did not use controls, making the results inconclusive

Genetic testing

There are different laboratory developed genetic tests to evaluate the risk of a patient with early or intermediate AMD progressing to advanced wet AMD within certain period of time

The idea is to be able to customize an approach to monitor and treat each individual based on their reported risk scores for disease progression

This allows for a more effective monitoring of patients

Gene therapy The idea is to replace or remove a defective gene to stimulate

the cell not to die and function properly again

Different abnormal genes related to AMD have been identified

The new gene is introduced into the retina via a virus (vector) , which deliver the genetic information for the rest of the patient’s life

Gene replacement therapy

Studies using animal models are now underway

Several companies are at the forefront of research into the use of gene therapy for wet AMD. These include Genzyme; Avalanche Biotechnologies, working with the Lions Eye Institute of Perth, Australia; and Oxford BioMedica, in partnership with Sanofi.

Macular degeneration and

stem cells On January 3, 2011, Advanced Cell Technology received a

FDA approval to treat advanced dry AMD using retinal pigment cells (RPE) from human embryonic stem cells

Uses a proprietary technique to extract a single cell from a young embryo allowing the rest to remain intact and develop normally

Phase1/2 study to determine the safety of RPE sub retinal implantation

UCLA, Wills Eye and Ear infirmary, Bascom Palmer Eye Institute and Massachusetts Eye and Ear.

July 9, 2012, FDA approved an increase of stem cell dosage to 100,000 RPE cells derived from human embryonic stem cells

June, 2012, a total of 16 patients started transplantation with Human Central nervous system stem cells ( non embryonic)

Study criteria: 50 years old or older Have no prior or current choroidal neovascularization Specific degree and extend of geographic atrophy No Diabetic retinopathy, cancer, glaucoma or autoimmune

disease

Allogenic cells ( another source other than the patient) and will receive immunosuppressive drugs X 3 months

4 patients have been transplanted with a single dose of 200,000 HuCNS-SC

Retina Foundation of the Southwest, Dallas, TX and Byers Eyes Inst., Stanford, Palo Alto, CA

January 2013 update: “No significant safety issues with human

embryonic stem cells in any of the 18 patients” “ 2 patients that has been treated showed some

signs of visual improvement and those gains in visual acuity have persisted for 18 months”

“ no signs of tumorigenicity, apparent rejection, ectopic tissue formation”

August 8, 2013 - The RIKEN Institute in Japan has started a clinical study for a wet AMD treatment derived from induced pluripotent stem cells (iPSC) —  mature cells that have been genetically reprogrammed to a stem cell-like state

Unfortunately, many wet AMD patients suffer irreversible vision loss by the time they are diagnosed.(3)

Because wet AMD progresses rapidly, at a rate of 18-20 µ per day (4), frequent monitoring is critical.

It is impractical for patients to visit their eye doctor as frequently as needed for earliest detection.

The most effective solution for early detection is home-based monitoring in addition to routine eye exams.

(3) Olsen, Ophthalmology 2004(4) Vander, Ophthalmology 1989

Importance of Early Detection

Amsler gridTo test each eye individually to

determine if there are any squiggly lines

or distortions in the grid

Normal Fundus Fluid and Lipid Hemorrhage

20/25 20/30 20/100

Therapeutic

window

By the time you notice symptoms or Amsler Grid changes

irreversible vision loss often has already occurred

Our brain will correct the signals received if assumes incomplete or inaccurate, making it extremely difficult for AMD patients to notice that something has gone wrong in their

retina until damage is profound

Early Detection of AMD

• The first FDA cleared home based telemonitoring system for AMD• Personalized patient monitoring, between physician exams• Designed for early detection, before noticeable symptoms & vision

loss• Preferential Hyperacuity Perimetry

• Demonstrated sensitivity, specificity• Robust normative database• Quantifies changes in metamorphopsia

The ForeseeHome was designed specifically for easy operation by AMD patients. It has received numerous awards for product design and its user friendly interface.

So what do we have to do?Do not smoke

Control your blood pressureGet regular physical activity such walking 30 minutes daily

Eat a variety of colors of fruits and vegetablesConsider natural sources of omega-3 fatty acids such tuna and wild

salmonTake AREDS 2 supplements

Protect you eyes with 100 % UV protection sun glassesUse a visor or a hat to block out more of the sun’s rays

www.geteyesmart.org